Heterocyclic substituted 2-acylamino-5-thiazoles, their preparation and pharmaceutical compositions containing them

ABSTRACT

Heterocyclic substituted 2-acylamino-5-thiazoles, their preparation and pharmaceutical compositions containing them. 
     A 2-Acylaminothiazole of formula: ##STR1## in which R 1  is H, an alkyl or a substituted alkyl; R IV  is a cycloalkyl, an aromatic group such as phenyl or a heterocyclic group which are unsubstituted or substituted; R V  is a substituted alkyl, a substituted carboxy such as an ester or an amide; or R IV  and R V  together represent a phenoxyalkylene group which may be substituted on the phenyl; and Z is a heterocyclic e.g. indolyl group; or a salt of compound (I).

This application is a division of Ser. No. 07/889,910, filed May 29,1992 now U.S. Pat. No. 5,314,889.

The present invention relates to heterocyclic derivatives which interactwith the cholecystokinin and gastrin receptor.

Cholecystokinin (CCK) is a polypeptide hormone which occurs in vivo inseveral forms containing 8 to 39 amino acids. It possesses manyphysiological activities with respect to the bile ducts, thegastrointestinal tract and on the central and peripheral nervoussystems, and reference may be made to the article by J. E. Morley inLife Sciences, 1982, 30, p. 479-493 which presents a detailed review ofits properties. Two different populations of CCK receptors have beendetected by means of specific antagonists; those of the A type which arepresent in particular in the pancreas, in the gall bladder and incertain zones of the central nervous system, while those of the B typeoccur mainly in the central nervous system.

Gastrin is a polypeptide hormone which acts in particular on the acidicsecretion of the stomach; its 5 C-terminal amino acids are identical tothose of CCK.

Gastrin and/or CCK-antagonising compounds have already been described,in particular proglumide, p-chlorobenzoyl-L-tryptophan, or morerecently, substituted benzodiazepines which are specific antagonistseither of the CCK A receptors, such as 3S(-)-N-2-[1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2-indolecarboxamide(J. Med. Chem., 1988, 31, 2235-46), or of the CCK B receptors, such as3R(+)-N-[1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N'-[3-methylphenyl]urea(Eur. J. Pharmacology, 1989, 162, 273-280).

Thiazole CCK-antagonists are described in P-A-0432 040.

Moreover, substituted thiazoles of formula: ##STR2## in which A₁represents a 2,4-dimethoxyphenyl; a 2,3,4-trimethoxyphenyl or aheterocyclic group such as a3,4-dihydro-7-methoxy-2,2,8-trimethylbenzopyran-1-2H-6-yl or a3,4-dihydro-7-methoxy-2,2-dimethylbenzopyran-1-yl-2H-6yl are describedin Indian J. Chem., Sec. B, 1988, 27 (B) 7, 629-32 as possessingbactericidal or fungicidal properties.

Other substituted thiazoles of formula: ##STR3## in which B₁ representshydrogen or a bromine atom are described in Chem. Pharm. Bull., 1977, 25(9), 2292-9 as possessing anti-inflammatory properties.

Other substituted thiazoles of formula: ##STR4## possess immunostimulantand anti-inflammatory properties and are described in Arch. Immunol.Ther. Exp., 1978, 26 (1-6), 921-9.

Substituted 4-quinolinecarboxamides of formula: ##STR5## are mentionedin Chem. Abst. 112 (13), 115 589 x as possessing bactericidal anddisinfectant properties.

The compounds according to the invention are heterocyclic substituted2-aminothiazoles of formula (I): ##STR6## in which R₁ represents ahydrogen atom; a (C₁ -C₄) alkyl group or a phenylalkylene group with a(C₁ -C₃) alkyl; an aminoalkylene group of formula --Z₁ --NR₄ R₅ in whichZ₁ represents a (C₂ -C₄) alkylene and R₄ and R₅ represent,independently, H or a (C₁ -C₄) alkyl or form with the nitrogen atom towhich they are attached, a saturated heterocycle such as morpholino,pyrrolidinyl, piperidino, piperazinyl or (C₁ -C₃) 4-alkylpiperazinyl; anoptionally esterified carboxyalkylene group of formula --Z₂ --COOR₆ inwhich Z₂ represents a (C₁ -C₄) alkylene and R₆ represents H or a (C₁-C₆) alkyl; a ( C₂ -C₅) cyanoalkylene group; a carbamoylalkylene groupof formula --Z₃ --CONR₇ R₈ in which Z₃ represents a (C₁ -C₄) alkyleneand R₇ and R₈ represent, independently, H or a (C₁ -C₄) alkyl, or withN, a heterocycle such as NR₄ R₅ ; a ( C₂ -C₆) hydroxyalkylene group, ora (C₁ -C₁₀) alkoxyalkylene group;

R_(IV) represents a (C₃ -C₇) cycloalkyl group which is unsubstituted orsubstituted by one or more (C₁ -C₄) alkyl groups; an aromatic group suchas a phenyl which is unsubstituted or which carries one or moresubstituents chosen from halogen atoms, in particular chlorine orfluorine, (C₁ -C₆) alkyl, and (C₁ -C₃) alkoxy and thioalkoxy groups,nitro and trifluoromethyl groups or such as a heterocycle containing atleast one heteroatom chosen from O, S and N in particular a furyl,thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyland thiazolyl, which are optionally substituted by a (C₁ -C₄) alkylgroup or a halogen atom or (C₁ -C₄) alkoxy or R_(IV) and R_(V), takentogether, represent the group: ##STR7##

bound through the phenyl carbon in position 4 of the thiazolyl ring andin which u equals 1 to 3, optionally carrying one or more (np)substituents Xp, which are identical or different, chosen from halogenatoms, (C₁ -C₃) alkyl and alkoxy groups, nitro and trifluoromethylgroups, np being equal to 0 to 3;

R_(V) represents a group --(CH₂)_(m) --X in which m is 0 to 5 and Xrepresents

a halogen atom, preferably a bromine atom, a hydroxyl, a (C₃ -C₇)cycloalkyl, a phenyl which may be substituted by one of the groupschosen from halogen atoms, (C₁ -C₄) alkyl or alkoxy groups, or nitro,amino, hydroxyl or trifluoromethyl groups;

a group chosen from --COOH; --COOX₁ ; --O--COX₁ ; --SCOX₁ ; (O)_(q)--S--X₁ with q=0.1 or 2; ##STR8## in which X₁ represents a (C₁ -C₅)alkyl; a phenyl which may be substituted by one or more groups chosenfrom halogen atoms, (C₁ -C₃) alkyl or alkoxy groups or nitro, amino,hydroxyl or trifluoromethyl groups; an adamantyl group;

a group chosen from --CONX₁ X₂ ; --NX₁ X₂ ; in which X₁ representshydrogen, a (C₁₃ -C₃) alkyl or a phenyl which is unsubstituted orsubstituted by one or more groups chosen from halogen atoms, (C₁ -C₃)alkyl or alkoxy groups, or nitro, amino, hydroxyl or trifluoromethylgroups and X₂ represents a hydrogen atom, a (C₁ -C₃) alkyl, oralternatively, X₁ and X₂ constitute, with the nitrogen atom to whichthey are attached, a heterocycle chosen from pyrrolidine or piperidinewhich is unsubstituted or substituted by an oxo group or by a hydroxylgroup, the latter being unsubstituted or substituted by an acyl, or by a--COOX₁ or --CONX₁ X₂ group;

or alternatively, R_(V) represents a (C₁ -C₅) alkoxy; a hydroxyl group;a cyclic amine with 5 or 6 members which is unsubstituted or substitutedby an oxo group or a hydroxyl group; a piperazinyl group which isunsubstituted or N-substituted by a group --COOAlk in which Alkrepresents a (C₁ -C₅) alkyl; a carboxylic acid group, a group --NX₂ X₄with X₄ ═H or X₄ ═--(CH₂)_(t) --X₅, with t equal to 2, 3 or 4 and X₅represents ##STR9## in which R₂ represents a (C₁ -C₄) alkyl; or a group--NR₂ R₃ with R₂ or R₃ representing independently H, (C₁ -C₆) alkyl, aphenyl group which is unsubstituted or substituted by one or moresubstituents chosen from halogen atoms or a (C₁ -C₃) alkyl group or a(C₁ -C₃) alkoxy group, or R₂ and R₃ constitute, with the nitrogen atomto which they are attached, a heterocycle with 5 or 6 members:

Z represents a heterocycle containing one or more heteroatoms chosenfrom O, S and N, coupled to an aromatic nucleus which may also contain aheteroatom chosen from O, S and N and which may be substituted by one ormore groups chosen from halogen atoms, (C₁ -C₃) alkyl and alkoxy groups,or benzyloxy, nitro, amino and trifluoromethyl groups, it being possiblefor the heteroatom N to be aromatic or in the form of --NH which isunsubstituted or substituted by (C₁ -C₄) alkyl, carboxyalkylene --Z₄--COOR₁₀ in which Z₄ represents (C₁ -C₄) alkylene and R₁₀ is H, benzylor (C₁ -C₆) alkyl; carbamoylalkylene --Z₅ --CONR₁₁ R₁₂ in which Z₅represents (C₁ -C₄) alkylene and R₁₁ and R₁₂ represent, independently,H, (C₁ -C₄) alkyl, or form with N a saturated heterocycle such asmorpholino or piperidino; acyl COR₁₃ with R₁₃ representing (C₁ -C₄)alkyl or phenyl; alkoxycarbonyl --COOR₁₄ with R₁₄ being tert-butyl orbenzyl;

as well as the addition salts of these compounds with inorganic ororganic acids and bases; the pharmaceutically acceptable nontoxic saltsare prepared but other salts which may be used to isolate or purify thecompounds of formula (I) are also within the invention.

The alkyl, alkylene, alkoxy and thioalkoxy groups may be linear orbranched.

Z represents in particular benzothienyl, benzofuranyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indolinyl,isoindolinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,cinnolinyl and [2,3-c]-thieno or [3,2-c]-pyridyl.

When Z represents an indolyl group of formula: ##STR10## in which(Xi)_(ni) represents the optional substituents of the aromatic nucleus,R₉ may represent H; a (C₁ -C₄) alkyl group; an optionally esterifiedcarboxyalkylene group of formula --Z₄ --COOR₁₀ in which Z₄ represents a(C₁ -C₄) alkylene and R₁₀ represents H, a benzyl or a (C₁ -C₆) alkyl; acarbamoylalkylene group of formula --Z₅ --CONR₁₁ R₁₂ in which R₁₁ andR₁₂ represent, independently, H or a ( C₁ -C₆) alkyl or form with N asaturated heterocycle chosen from morpholino or piperidino and Z₅ is a(C₁ -C₄) alkylene; an acyl group of formula COR₁₃ in which R₁₃represents a (C₁ -C₄) alkyl or a phenyl; an alkoxycarbonyl group offormula COOR₁₄ in which R₁₄ represents tert-butyl or benzyl.

Among the compounds of formula (I) , those in which R₁ representshydrogen are preferred and among these, more particularly those in whichZ represents an indolyl group which is substituted or unsubstituted onthe nitrogen; among the groups R_(IV), phenyl is preferred.

The subject of the present invention is also the preparation of thecompounds of formula (I) which are prepared by a coupling reaction of anaminothiazole of formula (II): ##STR11## in which R₁, R_(IV) and R_(V)have the meanings given for (I), under the usual conditions for theacylation of an amine group, with an acid of formula Z'COOH in which Z'represents Z or a substituted Z in which the reactive groups of Z havebeen protected, and R₁, R_(V), R_(IV) and Z have the same meaning as inthe formula (I), or with an activated form of the acid Z'COOH, such asan acid halide, an acid anhydride, and preferably a mixed anhydride suchas a carbonic anhydride, or an activated ester, obtained with thereagents commonly used in peptide synthesis.

The compounds (II) may be protected; in this case, R₁ ^(o) representsthe same substituents as R₁ in which the amino group which is present isN-protected, R_(IVa) and R_(Va) represent the same substituents asR_(IV) and R_(V) in which the hydroxyl or amino groups are O- andN-protected.

Once the groups have been protected, the appropriate deprotectionreaction is carried out, if necessary, after the condensation.

Numerous aminothiazoles of formula (II) are known.

The new aminothiazoles may be prepared according to one of the methodsdescribed in particular in Bull. Soc. Chim. (C) 1963, 2498-2503.

Generally, a thiourea will be reacted with an alpha-halogenated, andpreferably alpha-brominated ketone, according to the following reactionscheme: ##STR12##

R₁, R_(IV) and R_(V) having the same meaning as in the formula (II).

The preparation of various compounds (II) in which R₁ represents anaminoalkyl group is described in EP-A-0,283,390.

The alpha-halogenated ketones and the thioureas may be prepared bymethods the principles of which are described in the literature; thus,the alpha-brominated ketones (IV) may be prepared by reacting R_(V) CH₂COR_(IV) with bromine in acetic acid medium or with cuptic bromide in anorganic solvent such as ethyl acetate, a chlorine-containing solvent ormixtures thereof. The starting aromatic ketones are generally preparedby Friedel-Crafts reaction, whereas the aliphatic methyl ketones may beprepared by reacting diazomethane with appropriate carboxylic acidchlorides followed by hydrolysis of the corresponding diazoketone.

The alpha-chlorinated aromatic ketones may be prepared by Friedel-Craftsreaction with the appropriate alpha-chlorinated acid chloride.

When R_(V) represents an ester group (CH₂)_(m) --COOX₁, thecorresponding substituted thiazoles of formula (V) below in whichR_(IV), X₁ and m are as defined for (I) are known or are preparedaccording to known methods by reacting an alpha-bromoaceto acid or analpha-bromoketo ester with the thiourea according to the followingreaction scheme: ##STR13##

Depending on the value of the substituent R_(V), the following methodsof preparation are used:

a) when R_(V) represents a group --(CH₂)_(m) --OH, the correspondingsubstituted 2-aminothiazole of formula (VI) below, in which m is asdefined for (I), may be prepared from the above esters (V) by reductionwith an alkali metal hydride such as for example lithium aluminiumhydride in an aprotic solvent such as for example tetrahydrofuran togive the aminoalcohol of formula: ##STR14## the acylation of (VI) withZCOOH leads to the compound (Ib) of formula: ##STR15## in which formulaem, R_(IV) and Z are as defined for (I); b) when R_(V) represents anester group --(CH₂)_(m) --O--CO--X₁ or a thioester group --(CH₂)_(m)--S--COX₁ or (O)_(q) --S--X₁, in which m, X₁ and q are as defined for(I), the substituted 2-aminothiazoles (VII), (VIIc) or (VIId) in whichthe groups R_(IV), q, m, W and X₁ are as defined for (I), may beprepared

either according to the following Scheme 3: ##STR16## or fromN-protected alcohols (VI) such as defined above which are reacted withan acid chloride such as for example acetyl chloride in a solvent suchas for example pyridine, to obtain the esters of formula: ##STR17## inwhich X₁, m, R_(IV) or Z are as defined above for (I); c) when R_(V)represents a carbamate --(CH₂)_(m) --O--CO--NHX₁ in which m and X₁ areas defined for (I), the substituted thiazoles according to the inventionare prepared from the corresponding hydroxylated compounds (Ib), byreacting an isocyanate of formula X₁ --N═C═O, in an aprotic solvent suchas for example tetrahydrofuran or dichloromethane at a temperature ofbetween 20° C. and 100° C., to give the compound (If) of formula:##STR18## in which X₁, m, R_(IV) and Z are as defined for (I); d) whenR_(V) represents an amide --(CH₂)_(m) --CONX₁ X₂ in which m, X₁ and X₂are as defined for (I), the thiazoles according to the invention areprepared by reacting the amine NHX₁ X₂ with the corresponding ester offormula (V) or (Ia) in the presence or in the absence of a solvent suchas an alkanol, at a temperature of between 20 and 120° C.; the reactionmay also be carried out in a sealed tube depending on whether the amineis volatile, to give the compound (VIII) or (Ig) of formula: ##STR19##in which X₁, X₂, m, R_(IV) and, optionally, Z are as defined for (I);

e) when R_(V) represents an amine group --(CH₂)_(m) --NX₁ X₂, thesubstituted thiazoles according to the invention are prepared, forexample, by reduction of the abovedescribed amides of formula (VIII) byreduction with an alkali metal hydride such as for example lithiumaluminium hydride in a solvent such as tetrahydrofuran, at a temperatureof between 20° C. and the boiling temperature of the solvent, to givethe compound of formula: ##STR20## the acylation of (IX) with ZCOOHgives the compound (Ih) of formula: ##STR21## in which X₁, X₂, m, R_(IV)and Z are as defined for (I); f) when R_(V) represents a carbonate--(CH₂)_(m) --O--COOX₁, in which m and X₁ are as defined for (I), thethiazoles according to the invention are prepared from the alcohols (Ib)by reacting them with a chloroformate ##STR22## in the presence of abase such as triethylamine or pyridine, to give the compound (Ii) offormula: ##STR23## in which X₁, m, R_(IV) and Z are as defined for (I);g) when R_(IV) and R_(V) taken together represent the group: ##STR24##in which (X_(p))_(np) and u are as defined for (I), bound via the phenylcarbon in position 4 of the thiazole nucleus; for example, theintermediate 4-bromo-2H-dihydro-3,4-[1]-benzoxepin-5-one of formula:##STR25## is prepared according to G. Fontaine et al., C. R. Acad. Sci.,1965, 258, 4583; the2-amino-4,5-dihydro-[5,4-d]-thiazolo-[1]-benzoxepine of formula:##STR26## is prepared by cyclisation with the thiourea according to theusual method described above, and then acylated to give the compound offormula: ##STR27## in which Z is as defined for (I); h) when R_(V)represents an amino group --NX₂ X₄, in which X₂ and X₄ are as definedfor (I), the substituted thiazole according to the invention may beprepared from the 2-amino-5-bromothiazole of formula: ##STR28## which isprepared according to J. Chem. Soc., 1947, 114, which is then: eitheracylated, for example, with a substituted ZCOOH, in the presence of BOPand a base such as triethylamine, and then this brominated derivativeobtained of formula: ##STR29## in which R_(IV) and Z are as defined for(I), is substituted by an amine HNX₂ X₄ in an alkanol at a temperatureof between 20° C. and the boiling temperature of the solvent, to givethe compound of formula: ##STR30## in which X₂, X₁, R_(IV) and Z are asdefined for (I), or substituted by the amine HNX₂ X₄ and then acylatedin position 2 of the thiazole, the two reactions being carried out underidentical conditions to those described above;

i) when R_(V) represents a group --(CH₂)_(m) --X, in which m=0 and Xrepresents a (C₁ -C₅) alkoxy group

the corresponding 2-aminothiazole is prepared from2-bromo-2-alkoxy-1-phenylethanone, which is optionally substituted onthe phenyl, to give the product of formula: ##STR31## in which R_(IV) isas defined above and X represents a (C₁ -C₅) alkoxy, which is thenacylated as indicated above to give the compounds (Im) of formula:##STR32## in which R_(IV) and Z are as defined for (I) and X is asdefined above for (XI'), or one of their salts.

The compounds of formula (XI') are new intermediates which are alsowithin the invention.

Some of the acids ZCOOH or Z'COOH, are known and are even availablecommercially; the others are prepared using the methods known forsimilar molecules.

Thus, the indolecarboxylic acids, hereafter called Z"COOH; of formula:##STR33## in which R₉ represents an alkoxycarbonylalkylene group may beprepared from indolecarboxylic acids, which are commercially availableor which are obtained by conventional methods, using the reaction scheme4 below. ##STR34## in which Hal represents a halogen atom and Qrepresents a benzyl group.

The benzyl esters of scheme (4) are prepared by reacting thecorresponding acid with benzyl alcohol, in the presence of one of theacid group-activating agents which are commonly used in peptidesynthesis, such as:

1,1'-carbonyldiimidazole for which reference can be made to Synthesis1982, p. 833,

N,N-dicyclohexylcarbodiimide, in the presence of4-dimethylaminopyridine, for which reference can be made to J. Org.Chem. 1990, 55 (4), p. 1390,

benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate forwhich reference can be made to Synthesis, 1977, p. 413.

The base used during the binding of R₉ to the nitrogen of the benzylester is preferably an anhydrous strong base such as an alkali metalhydride; the reaction mixture is in this case an aprotic polar solvent,which is stable in the presence of a strong base such asdimethylformamide or dimethoxyethane; the reaction is carried out at atemperature of between about 15° C. and 80° C.

The removal of the benzyl group after the N-alkylation, is carried outin a conventional manner by reacting not less than one equivalent ofhydrogen, in the presence of a catalyst such as palladium on carbon,with the ester dissolved in an alcohol or dimethylformamide, optionallyunder a mild pressure.

Moreover, some ZCOOH acids are not very stable or carry a group whichmay react during the coupling with aminothiazole and it is preferable touse them in a protected form Z'COOH.

Thus, the derivatives (I) in which Z represents: ##STR35## and in which(X_(i))_(ni) represents the optional substituents, may be prepared fromthe compounds obtained by coupling the aminothiazole to compounds of theindolecarboxylic acid Z'COOH, of formula: ##STR36## in which Q'represents a group which is normally used for the protection of NH₂groups in amino acid coupling reactions, such as ##STR37## theprotective group Q may be removed from the compound of formula:##STR38## which is obtained after coupling to the derivative (II), byconventional deprotection methods.

BOC may be removed by pyrolysis, in the absence of solvent, at atemperature of between 180° and 200° C.

The indolecarboxylic acids Z"COOH in which R₉ is COOC(CH₃)₃ or COOCH₂ C₆H₅, may be prepared by reacting tert-butyl dicarbonate or benzylchloroformate with Z"COOH in which R₉ ═H, in the presence of a base suchas triethylamine or 4-dimethylaminopyridine, in a solvent such asacetonitrile or methylene chloride.

The acids Z"COOH in which R₉ is an acyl group, may be prepared byreacting the acid chloride or anhydride with Z"COOH, in which R₉ ═H, inthe presence of one equivalent of triethylamine and4-dimethylaminopyridine, for example in dichloromethane.

The acid chloride of formula ZCOCl, may be prepared, in particular byreacting SOCl₂ or a mixture of POCl₃ and P₂ O₅ with the correspondingacid, in general in the absence of solvent and at the reflux temperatureof the reaction mixture.

Among the activated esters of formula ZCOOY", Z'COOY" or Z"COOY", thosein which

Y" represents ##STR39## may be prepared by reacting1-hydroxybenzothiazole with the acid in the presence ofdicyclohexylcarbodiimide according to the procedure described in J. Am.Chem. Soc. 1971, 93, 6318-6319 (1971), or by reacting1-benzothiazolyloxytris(dimethylamino)phosphonium hexafluorophosphateaccording to the procedure described in Synthesis, 1976, 751-752.

The coupling of the aminothiazole (II) with the acid in activated esterform, may be carried out in a solvent the nature of which is chosenaccording to the solubility of the compounds and the type of activationof the acid group, preferably in the presence of a base, for example atertiary amine such as triethylamine; the reaction is generally carriedout at a temperature of between 0° C. and 30° C.

When the compounds of formula (I) contain a carboxylic acid group in Z,they are prepared by hydrolysis of an ester preferably in a base medium,for example by reaction of an inorganic base such as an alkali metalhydroxyl, in a dilute alcoholic medium or by acid hydrolysis in the caseof a tert-butyl ester.

The addition salts of the compounds of formula (I) with acids or basesare prepared in the usual manner by introducing the acid or the baseinto a solution of the compound of formula (I). The salt is isolated,depending on its solubility properties, after evaporation of the solventor addition of a non-solvent.

The compounds of formula (I) and their salts inhibit the binding ofcholecystokinin to its receptors. They are more or less selective forthe A or B type receptors, and for more or less potent gastrinantagonists.

Their affinity for the CCK A receptor has been determined in vitro usingthe method described below, the principle of which is that mentioned inLife Sciences, 1985, 37, (26), 2483-2490; it consists in determining thedisplacement of iodinated CCK 8S from its receptors, in a rat pancreashomogenate: aliquot amounts of pancreatic membrane suspension (100 μg ofproteins per ml) in a TRIS-HCl buffer (50 mM), of pH=7.4, containingMgCl₂ (5 mM), bacitracin (0.1 mg/ml), methylphenylmethanesulphonic acidfluoride (0.1 mg/ml), are incubated for 40 minutes at 25° C. in thepresence of iodinated CCK 8S (2000 Ci/mmol, equivalent to 50 mM finalconcentration) and of increasing concentrations of the test substance;the reaction is stopped by centrifugation after 40 minutes. Afterremoval of the supernatant, the radioactivity of the pellet is measured.Moreover, nonspecific binding is determined in the presence of CCK 8S ata concentration of 1 μM.

Under these conditions, the concentration inhibiting binding by 50%(IC₅₀) is less than 10⁻⁷ M for the products of the invention, and, formany, is about 10⁻¹⁰ M.

Their affinity for the CCK B receptors was determined by studying thedisplacement of iodinated CCK 8S from its specific receptors which arepresent in guinea pig cortex homogenates, using the same procedure asfor the CCK A receptors, but for a membrane suspension containing 600 μgof proteins/ml with a HEPES buffer (10 mM) at pH 6.5, containing NaCl(130 mM), MgCl₂ (5 mM), EDTA (1 mM) and bacitracin (250 mg/ml) and theincubation being for 2 hours.

At a concentration of 10⁻⁵ M, all the products displace more than 25% ofthe labelled CCK 8S from the B receptor; some have a IC₅₀ of about 10⁻⁹M.

The affinity for the gastrin receptor of the most CCK Breceptor-specific compounds was studied according to the methoddescribed below, the principle of which is that mentioned in J.Receptor. Res., 1983, 3 (5) 647-655; aliquots of guinea pig gastricglands in a HEPES buffer, pH=7.4 (24.5 mM), containing NaCl (98 mM), KCl(6 mM), NaH₂ PO₄ (2.5 mM), pyruvate (5 mM), CaCl₂ (0.5 mM), MgCl₂ (1mM), glucose (11.5 mM), glutamine (1 mM), bovine albumin (0.4 g/100 ml)were incubated for 90 minutes at 37° C. in a water bath in the presenceof iodinated gastrin (2-17) (2000 Ci/mmol; 70 pM) and of increasingconcentrations of the test products. The reaction was stopped bycentrifugation and the radioactivity of the pellet measured; thenon-specific binding was determined in the presence of gastrin (2-17) at1 μM. The compounds of the invention have a IC₅₀ of between 10⁻⁵ M and10⁻⁹ M.

It has also been shown that the compounds of the invention have aninhibitory activity with respect to that of CCK. This has beendemonstrated in vitro by measuring the inhibition by the test products,of CCK 8S-stimulated secretion of amylase by rat acinar cells, accordingto a method similar to that described in J. Biol. Chem., 1979, 254 (12),5321-5327, but with guinea pig pancreatic tissues. The compounds have aIC₅₀ of 10⁻⁶ M to 10⁻⁹ M.

Finally, in vivo, in mice, the compounds having a good affinity for theCCK A receptors antagonised the inhibition of the emptying of thestomach induced by subcutaneous administration of CCK 8S in theprocedure described in Life Sciences, 1986, 39, 1631-1638; the ED₅₀(effective dose 50) thus determined is substantially lower than that ofproglumide, a known gastrin antagonist.

As these compounds are not very toxic, they can be used as medicines forthe treatment of physiological disorders resulting from a hypersecretionof these peptides or from a dysregulation of the biological hormonalsystems in which they are involved, in the region of the intestinalsphere or in the central nervous system, depending on their specificity.Reference can be made to the review of the therapeutic applications ofthe antagonists of CCK and gastrin, published in "Proceedings ofInternational Symposium on Gastrin and Cholecystokinin" 7-11 Sept.1987--Ed. J. P. Bali, J. Martinez --Elsevier Science Pub. BV.

In particular, the antagonists of CCK will be useful in the treatment ofintestinal dyskinesias such as irritable colon syndrome, in thetreatment of acute or chronic pancreatitis or in that of pancreaticcarcinomas, but also for regulating appetite, or, combined withopium-containing analgesics, in the treatment of pain.

As for the more selective gastrin antagonists, they will be useful inthe treatment and prevention of gastric ulcers, in the treatment ofZollinger-Ellison syndrome, in that of hyperplasia of the G cells of theantrum or for patients with cancerous tumours of the oesophagus, of thestomach or of the intestine.

Among the antagonists of cholecystokinin at the level of the Areceptors, the following compounds are preferred:

2-[(1-Carboxymethyl-2-indolyl)carbonylamino]-4-phenyl-5-acetoxyethylthiazole.

2-[(2-Indolyl)carbonylamino]-4-phenyl-5-acetoxyethylthiazole.

The medicines according to the invention contain at least one of thecompounds of the formula (I) or one of its salts with a pharmaceuticallyacceptable acid or base, optionally combined with the usual excipientsso as to constitute a pharmaceutical composition which can beadministered in a conventional manner via the oral, transmucous,parenteral or rectal route. The doses administered depend on the natureand the severity of the disease, on the compound and on the route ofadministration. They will be generally between 20 and 100 mg per day inan adult man via the oral route and 3 to 10 mg by injection.

The pharmaceutical compositions according to the invention can be, fororal administration, provided in the form of tablets, pills, hardgelatin capsules or granules or alternatively in the form of asolution,. suspension or gel. For parenteral administration, thecompositions of the invention will be provided in the form of asolution, suspension or emulsion in an oil or any solvent for injection,optionally aqueous based containing conventional adjuvants for this typeof formulation.

For local administration, on the skin or on the mucous membranes, thecompositions according to the invention will be provided as a cream,ointment or in the form of a transdermal device, whereas for rectaladministration, they will be in the form of suppositories and rectalcapsules.

In the following text, examples of implementation of the invention aredescribed as well as methods of preparing certain synthesisintermediates of formula II and IV. The melting points, m.p., indicatedwere determined in capillary tubes. The nuclear magnetic resonance (NMR)spectra were recorded relative to tetramethylsilane.

PREPARATION A

2-Aminothiazole substituted in position 5 by a group --(CH₂)_(m) X₁

2-Amino-4-(2,4-dimethoxyphenyl ) -5-benzylthiazole ##STR40##

A) 1-(2,4-Dimethoxyphenyl)-3-phenylpropan-1-one is prepared according toE. Thomas et al., J. Med. Chem., 1985, 28, 442-446 via theFriedel-Crafts reaction.

B) 1-(2,4-Dimethoxyphenyl)-2-bromo-3-phenylpropan-1-one is preparedaccording to conventional methods by bromination using bromine in asolvent such as dichloromethane or carbontetrachloride.

C) 2-Amino-4-(2,4-dimethoxyphenyl)-5-benzylthiazole.

4.35 g of thiourea are added to 10 g of the brominated derivativeprepared above, dissolved in 100 ml of 95° ethanol and the reactionmixture is refluxed for three hours. The mixture is concentrated undervacuum and the residue is taken up in dichloromethane and then washedwith a saturated solution of Na₂ CO₃. The organic phase is separated bydecantation, dried over MgSO₄ and concentrated under vacuum. The residuecrystallises from 50 ml of dichloromethane.

m=7.10 g; m.p.=202°-203° C.

By carrying out the procedure as indicated above, the 2-aminothiazolesdescribed in Table 1 below are prepared.

                  TABLE 1                                                         ______________________________________                                         ##STR41##                                                                    X(CH.sub.2).sub.m                                                                           r.sub.4    r'.sub.4 m.p; °C.                             ______________________________________                                         ##STR42##    OCH.sub.3  OCH.sub.3                                                                              119                                          ##STR43##    OCH.sub.3  OCH.sub.3                                                                              163-164                                      ##STR44##    OCH.sub.3  OCH.sub.3                                                                              162                                          ##STR45##    OCH.sub.3  OCH.sub.3                                                                              121                                          ##STR46##    OCH.sub.3  OCH.sub.3                                                                              176                                         ______________________________________                                    

PREPARATION B

2-Aminothiazole substituted in position 5 by a group --(CH₂)--CO₂ X₁ or--(CH₂)_(m) --CH₂ OH

A) 2-Amino-4-phenyl-5-methoxycarbonylmethylthiazole.

(II): R₁ ═H; R_(IV) ═--C₆ H₅ ; R_(V) ═--CH₂ --CO₂ CH₃

Prepared according to E. Knott, J. Chem. Soc., 1945, 455.

B) 2-Amino-4-phenyl-5-hydroxyethylthiazole.

5 g of the amino ester prepared above is added to a suspension of 2 g oflithium aluminium hydride in 100 ml of tetrahydrofuran cooled to 0° C.,and the reaction mixture is refluxed for two hours. 2 ml of water, 1 mlof concentrated NaOH and 6 ml of water are then added successively aftercooling on an ice bath and then the reaction mixture is stirredovernight. The inorganic matter is separated by filtration and themother liquors are concentrated under vacuum. The residue is taken up indichloromethane, washed with water and the organic phase is successivelydecanted, dried over MgSO₄ and concentrated under vacuum. The residue ischromatographed on a silica gel, eluent: dichloromethane/methanol 100+3(v/v).

Concentration of the pure fractions gives 4 g of the expected alcohol.

m.p.=121° C.

By carrying out the procedure as indicated above, the 2-aminothiazolesdescribed in Table 2 below are prepared.

                  TABLE 2                                                         ______________________________________                                         ##STR47##                                                                    T           r.sub.4    r'.sub.4 m     m.p; °C.                         ______________________________________                                        CO.sub.2 CH.sub.3                                                                         H          H        1     231                                     OH          H          H        2     121                                     COOCH.sub.2 CH.sub.3                                                                      H          H        0     175                                     COOCH.sub.2 CH.sub.3                                                                      H          H        1     162                                     COOCH.sub.2 CH.sub.3                                                                      2-OCH.sub.3                                                                              4-OCH.sub.3                                                                            1     117-118                                 ______________________________________                                    

PREPARATION C

2-Aminothiazoles substituted in position 5 by a group ##STR48##

2-Amino-5-(1-adamantyl-1-carbonyloxyethyl)-4-phenylthiazole ##STR49##

A. 4-(1-Adamantylcarbonyloxy)-1-phenyl-1-butane.

The caesium salt of 1-adamantylcarboxylic acid is prepared according toJ. Org. Chem., 1977, 42, 8, 1286, from 12 g of 1-adamantylcarboxylicacid and 10.96 g of caesium carbonate. The salt obtained is dissolved in70 ml of DMF and then 18 g of 4-iodo-1-phenylbutan-1-one are added andthe reaction mixture is refluxed overnight. The DMF is evaporated undervacuum, and the residue resuspended in a 5% solution of Na₂ CO₃ andextracted with CH₂ Cl₂. The organic phase is washed with water and thendried over Na₂ SO₄. It is concentrated under vacuum and the residue ischromatographed on a silica gel, eluent: CH₂ Cl₂.

Concentration of the pure fractions gives 10 g of the expected compound.

B. 2-Amino-5-(1-adamantyl-1-carbonyloxyethyl)-4-phenylthiazole.

10 g of the compound prepared above are dissolved in 100 ml of CC₁ 4.4.9g of bromine dissolved in 50 ml of CCl₄ are added and the reactionmixture is left stirring for 30 minutes. It is washed with water, andthe organic phase decanted, dried over MgSO₄, filtered and concentratedunder vacuum. The residue is taken up in 50 ml of 95° ethanol. 3.9 g ofthiourea are added to the solution and the reaction mixture is leftovernight at room temperature. The mixture is concentrated under vacuum,and the residue is taken up in CH₂ Cl₂, washed with a 5% solution ofNaHCO₃, and the organic phase is decanted, dried over MgSO₄, filteredand concentrated under vacuum. The residue is taken up in ether anddried.

m=6.8g; m.p.=167° C.

By carrying out the procedure as indicated above, the 2-aminothiazolesdescribed in Table 3 below are prepared.

                  TABLE 3                                                         ______________________________________                                         ##STR50##                                                                    X.sub.1          m.p; °C.                                              ______________________________________                                         ##STR51##       109-110                                                       ##STR52##       129-130                                                       ##STR53##       147-149                                                       ##STR54##       190-192                                                       ##STR55##       107-108                                                      ______________________________________                                    

PREPARATION D

Aminothiazoles substituted in position 5 by a group --(CH₂)_(m) X inwhich X represents a group --NX₁ X₂ with X₁ ═X₂ ═H

Preparation of 2-amino-5-aminoethyl-4-phenylthiazole.

(II): R₁ ═H; R_(IV) ═C₆ H₅ ; R_(V) ═--CH₂ CH₂ NH₂

A) 4-Phthalimido-1-phenylbutan-1-one.

27.4 g of 4-iodo-1-phenylbutan-1-one and 27 g of potassium phthalimideare heated in 100 ml of DMF at 120° C. for 24 hours. The DMF isconcentrated under vacuum and the residue is successively washed withwater and with a 1N solution of NaOH and extracted with ethyl acetate.The organic phases are decanted, dried over MgSO₄, filtered andconcentrated under vacuum.

m=11 g.

B) 2-Amino-5-phthalimidoethyl-4-phenylthiazole.

9.6 g of the compound prepared above are dissolved in 50 ml of CCl₄ and80 ml of CH₂ Cl₂. A solution 5.6 g of bromine in 30 ml of CCl₄ is addeddropwise to the solution. The reaction mixture is washed with water, andthe organic phases are dried over MgSO₄, filtered and concentrated undervacuum. The residue is taken up 70 ml of ethanol, and 4.5 g of thioureaare added and the reaction mixture is left overnight at roomtemperature.

The mixture is cooled, and the hydrobromide is separated by filtration,washed with ethanol and then stirred vigorously in a 5% Na₂ CO₃ /ethylether mixture. The crystals are filtered.

m=8 g. F=208° C.

C) 2-Amino-5-aminoethyl-4-phenylthiazole.

8 g of the product prepared above are treated with 1.5 g of hydrazinehydrate dissolved in 100 ml of absolute ethanol. The reaction mixture isrefluxed overnight and then the following operations are carried outsuccessively: the ethanol is concentrated under vacuum, the residue istaken up in water, acidified by the addition of concentrated HCl up topH=1, the phtalazinedione separated by filtration, the aqueous phase,cooled on an ice bath, is alkalinised by the addition of concentratedNaOH up to pH=9, the precipitate is filtered, washed with water anddried in an oven.

m=3.7g; m.p.=136°-137° C.

PREPARATION E

2-Aminothiazoles substituted in position 5 by a group --(CH₂)_(m) X inwhich X represents a group --NX₁ X₂ in which X₁ ═H and X₂ ═--CO--CH₃

2-Amino-5-(2-acetylamino-1-ethyl)-4-phenylthiazole.

(II): R₁ ═H; R_(IV) ═--C₆ H₅ ; R_(V) ═CH₃ CONH(CH₂)₂ --

1 g of the 2-aminothiazole obtained according to Preparation D,dissolved in 60 ml of THF, in the presence of 0.7 ml of triethylamine,is treated with 0.44 ml of acetic anhydride dissolved in 20 ml of THF.The reaction mixture is left at room temperature for 2 hours andconcentrated under vacuum. The residue is washed with a 5% solution ofNaHCO₃, and the precipitate is separated by filtration, washed withwater and dried.

m=1.12 g; m.p.=208°-209° C.

Using the 2-aminothiazole obtained according to Preparation D, and bycarrying out the procedure according to Preparation E, the intermediatecompounds described in Table 4 below are prepared.

                  TABLE 4                                                         ______________________________________                                         ##STR56##                                                                    T                    m.p; °C.                                          ______________________________________                                         ##STR57##           157-158                                                   ##STR58##           oil                                                       ##STR59##           171                                                       ##STR60##           151                                                      ______________________________________                                    

PREPARATION F

2-Amino-4,5-dihydro-[5,4-d]-thiazolo-[1 ]-benzoxepin ##STR61##

A) 4-Bromo-4-2H-3,4-dihydro-[1]-benzoxepin-5-one is prepared accordingto G. Fontaine, P. Maitte, C. R. Acad. Sci., 1964, 258, 4583.

B) 2-Amino-4,5-dihydro-[5,4-d]-thiazolo-[1]benzoxepin.

2.05 g of thiourea are added to 0,027 mole of brominated derivativesolubilised in 100 ml of ethanol. The mixture is refluxed for 3 hours.The ethanol is evaporated, the residue is taken up in an aqueoussolution of sodium carbonate. It is extracted with ethyl acetate, andthe organic phase is dried over Na₂ SO₄ and evaporated to dryness. 2.4 gof white crystals are obtained.

m.p.=216° C.

PREPARATION G

2-Aminothiazoles substituted in position 5 by a group --(CH₂)_(m) --X inwhich m=0 and X represents a (C₁ -C₅) alkoxy group or a halogen##STR62##

(II): R₁ ═H; R_(IV) ═--C₆ H₅ ; R_(V) ═--OCH₃

15.65 g of 2-bromo-2-methoxy-1-phenylethanone and 5.52 g of thiourea aredissolved in 70 ml of methanol. The reaction mixture is refluxedovernight and then concentrated under vacuum. The residue is taken up ina 10% solution of Na₂ CO₃ in water, the mixture is extracted with CH₂Cl₂, the organic phase is separated and successively dried over Na₂ SO₄,filtered and concentrated under vacuum. The residue is recrystallisedfrom isopropyl ether.

m=7.5g; m.p.=96° C.

                  TABLE 5                                                         ______________________________________                                         ##STR63##                                                                           r.sub.4                                                                              m.p; °C.                                                 ______________________________________                                               2-Cl   72                                                                     2-OCH.sub.3                                                                          159-160                                                                4-CH.sub.3                                                                           112-114                                                         ______________________________________                                    

PREPARATION H

Preparation of the indolecarboxylic acids

A) 1-tert-butyloxycarbonylmethylindole-2-carboxylic acid.

a) Benzyl indole-2-carboxylate.

5 g of N,N'-carbonyldiimidazole are introduced into a solution of 5 g ofindole-2-carboxylic acid in 50 ml of dry tetrahydrofuran; after stirringfor 12 hours at room temperature, 3.7 g of benzyl alcohol are added andthe reaction mixture is heated at its reflux temperature; the latter ismaintained for 8 hours before removing the solvent by distillation underreduced pressure. The residue is dissolved in ethyl acetate and theorganic phase is washed with a 1N aqueous solution of NaOH and thendried before evaporation of the solvent.

The yellow residue is recrystallised from isopropanol.

m.p.=136° C.; yield=85%.

b) Benzyl 1-tert-butoxycarbonylmethylindole-2carboxylate.

80% sodium hydride in oil is added in portions (0.075 mole; 2.25 g) to asolution of benzyl indole-2-carboxylate (0.072 mole; 18.18 g) in 200 mlof dimethylformamide, under a nitrogen atmosphere, at a temperature ofbetween 0° C. and 5° C. The mixture is allowed to reequilibrate to roomtemperature and the mixture is stirred for 1 hour. tert-Butylbromoacetate (0.072 mole; 14 g) is then added dropwise at 10° C. Thereaction mixture is left for 3 hours at room temperature. Thedimethylformamide is evaporated and the residue is successively taken upin water, extracted with methylene chloride, and the organic phase driedover sodium sulphate and evaporated to dryness. 23.8 g of white crystalsare obtained by crystallisation of the residue from diisopropyl ether.

m.p.=95° C.

c) 1-tert-Butoxycarbonylmethylindole-2-carboxylic acid.

The ester prepared above (0.065 mole; 23.8 g) is solubilised in amixture of 400 ml of ethanol and 100 ml of dimethylformamide. 1 g of 5%palladium on carbon is added and the mixture is hydrogenated underatmospheric pressure at room temperature. After stirring for 30 minutes,the theoretical volume of hydrogen is absorbed. The catalyst is filteredon talc and the solvents are evaporated to dryness. A crystallisedresidue is obtained, which is washed with diisopropyl ether. 15.3 g ofwhite crystals are obtained.

m.p.=177° C.

B) 1-Acetylindole-2-carboxylic acid.

A mixture of indole-2-carboxylic acid (0.06 mole; 10 g), triethylamine(0.15 mole; 21.25 g), acetic anhydride (0.075 mole; 7.5 g) and4-dimethylaminopyridine (0.006 mole; 0.8 g), in methylene chloride isstirred at room temperature for 18 hours. The reaction mixture is thenpoured into an aqueous solution of buffer pH=2. The precipitate formedis filtered and then dried in an oven under vacuum. The methylenechloride phase is decanted, dried over sodium sulphate and evaporated to3/4. A second crop of 1-acetylindole-2-carboxylic acid precipitates. Thetwo crops are combined to give 9.4 g of beige crystals.

m.p.=168° C.

C) 1-Benzyloxycarbonylaminoindole-2-carboxylic acid.

8 g of indole-2-carboxylic acid are dissolved in 120 ml ofdichloromethane and then 10 g of triethylamine and 1 g of4-dimethylaminopyridine are added.

The reaction mixture is stirred and then cooled to 0°-5° C. 8.5 g ofbenzyloxycarbonyl chloride are added dropwise at a temperature of lessthan 5° C. The mixture is left stirring overnight and then concentratedunder vacuum. The residue is taken up in 500 ml of ethyl acetate andthen filtered. The mother liquors are concentrated under vacuum andtaken up in 50 ml of dichloromethane. The mother liquors are filteredand concentrated under vacuum.

m=2.4 g of oil; NMR (DMSO): 2 H at 5.38 (s, CH₂ --C₆ H₅); 10 H between7.0 and 8.0 (m; Har).

D) 1-tert Butyloxycarbonylindole-2-carboxylic acid

30 ml of a solution of 6 g of di-tert-butyl dicarbonate are introduceddropwise into 30 ml of a solution of 4 g of indole-2-carboxylic acid, 4ml of triethylamine and 0.4 g of 4-dimethylaminopyridine inacetonitrile. After stirring for 2 hours at room temperature andremoving the precipitate formed, the acetonitrile is removed bydistillation and the reside is dissolved in methylene chloride. Theorganic phase is washed with water, dried and concentrated to dryness.

m.p.=117° C.; yield 66%; yield=66%.

EXAMPLE 12-[(2-Indolyl)carbonylamino]-4-(2,4-dimethoxyphenyl)-5-benzylthiazole##STR64##

1.96 g of 2-amino-4-(2,4-dimethoxyphenyl)-5-benzylthiazole preparedabove according to Preparation A, 1.22 g of 1-acetylindole-2-carboxylicacid, 0.85 g of triethylamine and 2.95 g of BOP are dissolved in 20 mlof dimethylformamide.

The reaction mixture is stirred for 24 hours at room temperature andthen poured into a buffer solution, pH=2. A yellow precipitate isseparated by filtration, washed with water and dissolved in ethylacetate. The solution is washed successively with a buffer solution,pH=2, with water, with a 5% solution of NaHCO₃ and with water, and thendried over MgSO₄ and concentrated under vacuum. The residue is purifiedby chromatography on a silica gel, eluent: dichloromethane/ethyl acetate98/2 (v/v).

Concentration of the pure product fractions gives a residue which istreated, with stirring for 24 hours, with 3 g of Na₂ CO₃ in 80 ml ofmethanol. The methanol is concentrated under vacuum and the residue istaken up in a water/ether mixture. A white precipitate is separated byfiltration and washed with ether.

m=0.97 g; m.p.=201°-202° C.

The compounds according to the invention, which are described in Table 6below, are prepared in the same manner.

                  TABLE 6                                                         ______________________________________                                         ##STR65##                                                                    Example n°                                                                          R.sub.V       m.p; °C.                                    ______________________________________                                                      ##STR66##    225                                                3                                                                                           ##STR67##    272                                                4                                                                                           ##STR68##    262                                                5                                                                                           ##STR69##    225                                                6                                                                                           ##STR70##    283                                                ______________________________________                                    

EXAMPLE 7 2-[(1-tert-Butoxycarbonyloxymethyl-2-indolyl)carbonylamino]-4-phenyl-5-hydroxyethylthiazole. ##STR71##

2 g of the aminoalcohol prepared above (according to Preparation B,Table 2), 2.75 g of 1-tert-butoxycarbonylindole-2-carboxylic acid, 1.4 gof triethylamine and 4.9 g of BOP are dissolved in 15 ml ofdimethylformamide. After leaving overnight at room temperature, thereaction mixture is poured into phosphate buffer, pH=2. A precipitate isseparated by filtration, washed with water and dissolved in ethylacetate. The solution is successively washed with a 5% solution ofNaHCO₃ and with water, separated by decantation, and the organic phaseis dried over MgSO₄ and concentrated under vacuum.

The residue is purified by chromatography on a silica gel, eluent :dichloromethane/methanol 100+0.5 (v/v).

The first product eluted corresponds to the deacylated compound (O and Nacylation, m.p.=70° C.).

The expected product is the second to be eluted.

m=1.2 g; m.p.=180°-181° C.

EXAMPLE 82-[(1-tert-Butoxycarbonylmethyl-2-indolyl)carbonylamino]-4-phenyl-5-acetoxyethylthiazole##STR72##

0.30 g of the product prepared above is suspended in 5 ml of pyridine.

1.2 ml of acetic anhydride are added and the reaction mixture is stirredovernight at room temperature. The mixture is then poured into sulphatebuffer, pH=2, and a precipitate is separated by filtration, washed withwater and then taken up in dichloromethane. The solution is successivelywashed with a 5% solution of NaHCO₃, separated by decantation, and theorganic phase is dried over MgSO₄, filtered and concentrated undervacuum. The residue is purified by chromatography on a silica gel,eluent: dichloromethane/ethyl acetate 98/2 (v/v).

m=0.16g; NMR (DMSO): 9 H at 1.48 (S, t-BuO₂ C); 3 H at 2.00 (S, CH₃CO₂); 2 H at 3.24 (T, J=7 Hz, CH₂ thiazole); 2 H at 4.30 (T, J=7 Hz, CH₂OAc); 2 H at 5.40 (S, CH₂ CO₂ t-Bu ); 10 H between 7.2 and 7.9 (M, Bar);1 H at 12.8 (S, NHCO).

EXAMPLE 9 2-[(1-Carboxylmethyl-2-indolyl)carbonylamino]-4-phenyl-5-acetoxyethylthiazole ##STR73##

0.15 g of the compound prepared above is solubilised in 2 ml of anisoleand 10 ml of trifluoroacetic acid.

The mixture is left for 45 minutes at room temperature and thenconcentrated under vacuum. The residue obtained is washed with a mixtureof hexane and diethyl ether (50/50) and then dried.

m=0.14g; m.p.=217°-218° C.

EXAMPLE 102-[(1-Acetyl-2-indolyl)carbonylamino]-4-(2,4-dimethoxyphenyl)-5-ethoxycarbonylmethylthiazole##STR74##

1.5 g of 2-amino-4-(2,4-dimethoxyphenyl)-5-ethoxycarbonylmethylthiazole,1 g of 1-acetylindole-2carboxylic acid, 0.7 ml of triethylamine and 2.39g of BOP are dissolved in 15 ml of dichloromethane. The reaction mixtureis stirred overnight at room temperature and then concentrated undervacuum. The residue is taken up in ethyl acetate and the solution issuccessively washed with a buffer solution, pH=2, with a 5% solution ofNaHCO₃ and with water, and then the organic phase is dried over MgSO₄and concentrated under vacuum. The residue is purified by chromatographyon a silica gel, eluent: dichloromethane/ethyl acetate 100/2.5 (v/v).

m=1.2 g; m.p.=130°-135° C.

EXAMPLE 112-[(2-Indolyl)carbonylamino]-5-ethoxycarbonyl-4-phenylthiazole ##STR75##

By carrying out the procedure according to Example 10 which is describedabove, the compound 2-[(1-acetyl-2-indolyl )carbonylamino]-4-phenyl-5-ethoxycarbonylthiazole (1.5 g) is prepared anddissolved in 100 ml of ethanol in the presence of 0.6 g of Na₂ CO₃. Themixture is stirred at room temperature for 48 hours and thenconcentrated under vacuum. The residue is triturated in water and thenin a minimum amount of dichloromethane, filtered and dried.

m=1.1 g; m.p.=248° C.

EXAMPLE 122-[(2-Indolyl)carbonylamino]-4-(2,4-dimethoxyphenyl)-5-carboxymethylthiazol##STR76##

0.5 g of2-[(1-acetyl-2-indolyl)carbonylamino]-4-(2,4-dimethoxyphenyl)-5-ethoxycarbonylmethylthiazole,prepared above according to Example 10, is dissolved in 10 ml of 95°ethanol and then 1.5 ml of 2N NaOH are added. The reaction mixture isstirred,overnight at room temperature and then concentrated undervacuum. The residue is taken up in a buffer solution, pH=2, aprecipitate is separated by filtration, washed with water, filtered andthen rinsed with ether.

m=0.28g; m.p.=284° C.

By carrying out the procedure according to Examples 7 to 12 above, thecompounds described in Table 7 below are prepared.

                  TABLE 7                                                         ______________________________________                                         ##STR77##                                                                    Example No.                                                                            T            m     R.sub.9   m.p.; °C.                        ______________________________________                                        13       CO.sub.2 CH.sub.3                                                                          1     H         254                                     14       CO.sub.2 CH.sub.3                                                                          2     H         181                                     15       OH           2     CH.sub.2 CO.sub.2 H                                                                     131                                     16       OH           2     H         242                                     17       OH           3     H         213                                     18       OCOCH.sub.3  2     H         168                                     19       OCOCH.sub.3  3     H         192                                     20       OCOC.sub.6 H.sub.5                                                                         2     CH.sub.2 CO.sub.2 H                                                                     216                                     21       OCO-tert-Bu  2     H         229                                     22       CO.sub.2 H   1     H         266                                     23       CO.sub.2 H   2     H         >300                                    24       CO.sub.2 H   2     CH.sub.2CO.sub.2 H                                                                      239-240                                 25       CO.sub.2 H   1     CH.sub.2CO.sub.2 H                                                                      199-200                                 26        CO.sub.2 CH.sub.3                                                                         2     CH.sub.2CO.sub.2 H                                                                      202-203                                 27       CO.sub.2 CH.sub.3                                                                          1     CH.sub.2CO.sub.2 H                                                                      183-185                                 28                                                                                      ##STR78##   1     CH.sub.2CO.sub.2 H                                                                      252                                     29                                                                                      ##STR79##   1     CH.sub.2CO.sub.2 H                                                                      233-234                                 30                                                                                      ##STR80##   1     CH.sub.2CO.sub.2 H                                                                      241-242                                 ______________________________________                                    

EXAMPLE 312-[(2-Indolyl)carbonylamino]-4-phenyl-5-[2-(1-pyrrolidinocarbonyl)-1-ethyl]thiazole##STR81##

0.5 g of the ester described in Example 14 is added to 5 ml ofpyrrolidine, the mixture is stirred overnight at room temperature andthen poured into a buffer solution, pH=2. A precipitate is separated byfiltration and then dissolved in ethyl acetate. The solution is washedwith a buffer solution, pH=2, and then with water, and the organic phaseis separated by decantation, dried over MgSO₄ and concentrated undervacuum.

m=0.48g; m.p.=179° C.

By carrying out the procedure according to Example 10 above, compounds32 to 51, which are described in Table 8 below, are prepared.

                  TABLE 8                                                         ______________________________________                                         ##STR82##                                                                    Example                                                                       No.     T                 m     r.sub.4                                                                             m.p.; °C.                        ______________________________________                                        32      COOCH.sub.3       1     4-F   224-225                                 33      COOC.sub.2 H.sub.5                                                                              1     2-Cl  178                                     34                                                                                     ##STR83##        1     H     180                                     35                                                                                     ##STR84##        1     H     239                                     36                                                                                     ##STR85##        1     4-F   243-244                                 37                                                                                     ##STR86##        1     2-Cl  187-188                                 38      NH.sub.2          2     H     202-203                                 39                                                                                     ##STR87##        2     H     261-262                                 40                                                                                     ##STR88##        2     4-F   188-189                                 41                                                                                     ##STR89##        2     H     208-209                                 42                                                                                     ##STR90##        2     H     223-224                                 43                                                                                     ##STR91##        2     H     264                                     44                                                                                     ##STR92##        2     H     248-249                                 45                                                                                     ##STR93##        2     H     275-276                                 46                                                                                     ##STR94##        2     H     209-210                                 47                                                                                     ##STR95##        2     H     196-197                                 48                                                                                     ##STR96##        2     H     218-219                                 49                                                                                     ##STR97##        2     H     140-142                                 50                                                                                     ##STR98##        2     H     270-271                                 51                                                                                     ##STR99##        2     H     212-213                                 ______________________________________                                    

EXAMPLE 522-[(2-Indolyl)carbonylamino]-4-phenyl-5-phenylaminocarbonyloxyethylthiazole##STR100##

A)2-[(1-Acetyl-2-indolyl)]carbonylamino-4-phenyl-5-phenylaminocarbonyloxyethylthiazole.

0.7 g of the alcohol prepared according to Example 16 and 0.2 ml ofphenyl isocyanate are stirred overnight at room temperature in 5 ml ofdichloromethane. The precipitate formed is separated by filtration andthen purified by chromatography on a silica gel, eluent:dichloromethane/ethyl acetate 95/5 (v/v).

m=0.52 g; m.p.=156° C.

B) Compound 52

0.5 g of the compound prepared above is dissolved in 30 ml of ethanoland 5 ml of water and then 0.21 g of Na₂ CO₃ is added.

The reaction mixture is stirred overnight at room temperature and thenconcentrated under vacuum. The residue is taken up in ethyl acetate andwashed successively with a solution of Na₂ CO₃ and with water. Theorganic phase is separated by decantation and concentrated under vacuum.The residue is taken up in ether.

m=0.4 g; m.p.=249° C.

EXAMPLE 532[(2-Indolyl)carbonylamino]-4,5-dihydro-[5,4-d]-1H-thiazolobenzoxepin##STR101##

1 g of the thiazole prepared above (Preparation F), 2.6 g of BOP, 0.93 gof 1-acetylindole-2-carboxylic acid and 0.46 g of triethylamine aremixed in 30 ml of dimethylformamide. The reaction mixture is stirred for30 hours at room temperature. The dimethylformamide is evaporated, andthe residue is taken up in ethyl acetate and washed with water. Theorganic phase is dried over sodium sulphate and evaporated. The residueis chromatographed on a silica gel, eluent: dichloromethane/methanol100+0.5 (v/v). 0.9 g of a yellow foam is obtained and it is solubilisedin dichloromethane to which ethanol (100 ml) has been added. 10 ml of 2NNaOH are added and the mixture is stirred at room temperature for 1hour. After evaporation of the organic solvents, the residue is taken upin ethyl acetate and washed with a buffer solution, pH=2. The organicphase is dried over MgSO₄, filtered and evaporated. Yellow crystals areobtained which are then washed with dichloromethane and then withethanol.

m=0.45 g; m.p. >260° C.

EXAMPLE 542-[(2-Indolyl)carbonylamino]-4-phenyl-5-(1-piperidinyl)thiazole##STR102##

A) 2-Amino-4-phenyl-5-(1-piperidinyl)thiazole.

A mixture of 1 g of 2-amino-4-phenyl-5-bromothiazole and 1.7 g ofpiperidine in 25 ml of absolute ethanol is refluxed for 48 hours. Theethanol is concentrated under vacuum and the residue is taken up in 50ml of water and 10 ml of 30% NaOH. It is extracted with ethyl acetate,and the organic phase is dried over Na₂ CO₄ and filtered. The solutionis concentrated under vacuum and the residue is recrystallised fromisopropyl ether.

m=0.41 g; m.p=135°-137° C.

B) Compound 54

0.4 g of the product obtained above is dissolved in 50 ml ofdichloromethane. 0.33 g of 1-acetylindole-2-carboxylic acid, 0.82 g ofBOP and 0.19 g of triethylamine are added successively. The reactionmixture is stirred for 4 days at room temperature. 25 ml of water areadded and the organic phase is separated by decantation, dried over Na₂SO₄ and concentrated under vacuum. The residue is taken up in 50 ml ofabsolute ethanol, and 10 ml of 2.5N NaOH are added and the mixture isstirred for 3 hours at room temperature. The mixture is concentratedunder vacuum, and the residue is taken up in 50 ml of water, extractedwith ethyl acetate, and the organic phase is separated by decantation,dried over Na₂ SO₄ and concentrated under vacuum. The residue isrecrystallised from ethyl acetate.

m=0.26 g; m.p. >260° C.

By carrying out the procedure according to Example 54, the compounds 55and 56, which are described in Table 9 below, are prepared.

                  TABLE 9                                                         ______________________________________                                         ##STR103##                                                                   Example No.                                                                              R.sub.V            m.p.; °C.                                ______________________________________                                        55                                                                                        ##STR104##        >300                                            56                                                                                        ##STR105##        247-249                                         ______________________________________                                    

EXAMPLE 57 2-[(2-Indolyl)carbonylamino]-5-bromo-4-phenylthiazole##STR106##

3.9 g (0.015 mole) of 2-amino-5-bromothiazole are dissolved in 60 ml ofdichloromethane.

3.26 g of 1-acetylindole-2-carboxylic acid, 8.1 g of BOP, 1.85 g oftriethylamine are added, and the reaction mixture is stirred at roomtemperature for 8 days and then 100 ml of an aqueous solution which isbuffered to pH=2 are added, and the mixture is decanted, and the organicphase is dried over Na₂ SO₄ and concentrated under vacuum. The residueis taken up in 100 ml of methanol and then 5 g of Na₂ CO₃ are added. Themixture is stirred for three hours at room temperature, concentratedunder vacuum at low temperature, and taken up in 100 ml of an aqueoussolution which is buffered to pH=2, extracted with ethyl acetate and theorganic phase is dried over Na₂ SO₄. The mixture is filtered andconcentrated under vacuum. The residue is chromatographed on a silicagel, eluent: CH₂ Cl₂. After removing the top impurities, the expectedproduct is eluted, and it is recrystallised, after evaporation of thesolvent, from a CH₂ Cl₂ /diisopropyl ether mixture.

m=2.8g; m.p.=224°-226° C.

EXAMPLE 58 2-[(2-Indolyl)carbonylamino]-5-methoxy-4-phenylthiazole##STR107##

3.15 g of 2-amino-5-methoxy-4-phenylthiazole are dissolved in 60 ml ofCH₂ Cl₂. 3.26 g of 1-acetylindole-2-carboxylic acid, 8.12 g of BOP and1.86 g of triethylamine are added, and the reaction mixture is stirredat room temperature for one week. 50 ml of water are added and theorganic phase is decanted, dried over Na₂ SO₄, filtered and concentratedunder vacuum. The residue is taken up in 100 ml of methanol, and 10 g ofK₂ CO₃ are added and the mixture is stirred overnight at roomtemperature. The mixture is concentrated under vacuum, and the residueis taken up in water, and the precipitate formed is separated byfiltration and washed with CH₂ Cl₂.

m=1.7 g; m.p. >260° C.

By carrying out the procedure according to the example above, thecompounds 59 to 61, which are described in Table 10 below, are prepared.

                  TABLE 10                                                        ______________________________________                                         ##STR108##                                                                   Example No.     r.sub.4  m.p.; °C.                                     ______________________________________                                        59              2-Cl     260-262                                              60              4-CH.sub.3                                                                             252-254                                              61              2-OCH.sub.3                                                                            248-250                                              ______________________________________                                    

EXAMPLE 62 2-[(2-Indolyl)carbonylamino]-5-hydroxy-4-phenylthiazole##STR109##

0.58 g of the thiazole prepared according to Example 58 are dissolved in100 ml of CH₂ Cl₂. 4.98 ml of a 2M solution of boron tribromide in CH₂Cl₂ are added at room temperature and the reaction mixture is leftstirring for 24 hours. 4.98 ml of BBr₃ are again added, the mixture leftfor 5 days at room temperature and 4.98 g of BBr₃ are finally added andthe reaction mixture is left at room temperature for 48 hours. It isthen adjusted to pH=5-6 by the addition of a 4N solution of NaOH andthen the organic phase is extracted with 2 times 50 ml of 4N NaOH. Theaqueous phase is neutralised by adding a 2N solution of HCl. The mixtureis extracted with CH₂ Cl₂, and the organic phases are dried over Na₂SO₄, filtered and concentrated under vacuum to produce a residue whichcrystallises.

m=0.5g; m.p.=237°-239° C.

We claim:
 1. A 2-acylaminothiazole of formula: ##STR110## in whichR_(IV) is selected from the group consisting of (C₃ -C₇) cycloalkyl, (C₁-C₄)alkyl substituted (C₃ -C₇)cycloalkyl, phenyl and phenyl substitutedby one or more groups selected from halogen, (C₁ -C₆) alkyl, (C₁-C₃)alkoxy, (C₁ -C₃)thioalkoxy, nitro and trifluoromethyl, andX isselected from the group consisting of (C₁ -C₅)alkoxy, piperidinyl,4-hydroxy piperidinyl and 4-(C₁ -C₃)-alkoxycarbonyl piperazinyl.
 2. Acompound of formula: ##STR111## in which R_(IV) is selected from thegroup consisting of (C₃ -C₇)cycloalkyl, (C₁ -C₄)alkyl substituted (C₃-C₇)cycloalkyl, phenyl and phenyl substituted by one or more groupsselected from halogen, (Cl-C₆) alkyl, (C₁ -C₃) alkoxy, (C₁-C₃)thioalkoxy, nitro and trifluoromethyl,m is selected from 1 and 2,and --NX₁ X₂ is selected from the group consisting of phtalimido and--NH₂, or a salt thereof.